Diazotricyclododecanes

ABSTRACT

1. 3,7 - BIS(2-HYDROXYETHYL)-3,7-DIAZATRICYCLO(4.2.2.2**2,**5)DODECANE-4,8-DIONE.

United States Patent 3,562,252 DIAZOTRICYCLODODECANES Leo A. Paquette, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed July 16, 1962, Ser. No. 210,196

Int. Cl. C07d 53/00 US. Cl. 260-239.3 3 Claims This invention relates to novel compositions of matter and to methods for their preparation and is particularly directed to certain diazatricyclododecanes and their preparation.

The novel diazatricyclododecanes of the invention are represented by the following structural formula:

wherein R is selected from the group consisting 01 hydrogen, methyl, and ethyl; R is selected from the group consisting of hydrogen, methyl, and ethyl; R is selected from the group consisting of hydrogen, methyl, and ethyl; R is selected from the group consisting of hydrogen, methyl, and ethyl; and R contains from 1 to 12 carbon atoms, inclusive and is selected from the group consisting of alkyl, cycloalkyl, ar alkyl, hydroxyalkyl, alkoxyalkyl, and (alkoxyl) -aralkyl wherein n is an integer from 1 to 3, inclusive. Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, and the isomeric forms thereof. Examples of cycloalkyl are cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclopentylpropyl, cyclononyl, bornyl, fenchyl and cyclododecyl. Exampes of aralkyl are benzyl, phenethyl, l-phenethyl, and 3-phenylpropyl.

The novel diazatricyclododecanes of the invention are nitrogenous bases and as such can exist in both the protonated and nonprotonated form according to the pH of the environment. The nonprotonated form can be oxidized, with hydrogen peroxide for example, to form the N-oxide. The N-oxide also can exist in both the protonated and nonprotonated form according to the pH of the environment. The protonated forms can be isolated as acid addition salts which are useful for upgrading the free base and free base N-oxide forms, i.e., the nonprotonated forms. Suitable acids for this purpose are hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fiuosilicic acid, picric acid, Reineckes acid, azobenzenesulfonic acid, and the like. The acid addition salt can be formed by neutralizing the free base or free base N-oxide with the appropriate acid or by metathesis of a simple acid addition salt such as the hydrochloride or sulfate with another salt of the desired acid.

The novel diazatricyclododecanes of the invention are useful intermediates. Thus, the condensation products obtained from the thiocyanic acid addition salts and formaldehyde according to US. Pats. 2,425,320 and 2,606,155 are useful as pickling inhibitors, and the fiuosilicic acid addition salts are useful as mothproofing agents according to US. Pats. 1,915,334 and 2,075,359.

The novel compounds of the invention can also exist in the form of quaternary ammonium salts, such for ex ample, as those obtained by coordinating the free base form with a lower-alkyl halide, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl chloride, including the isomers thereof. The quaternary ammonium salts are useful for forming the corresponding fiuosilicic acid salts which are useful as mothproofing I II wherein R R R R and R are as given above. The latter compounds (Formula II) can be prepared by hydrogenating with hydrogen in an organic solvent, for example, acetic acid or a lower-alkanol, in the presence of a catalyst effective to saturate olefinic double bonds, for example, platinum or palladium oxides, a compound having the following structure:

III

wherein R R R R and R are as given above.

The intermediate III can be prepared by the photodirnerization of a Z-pyridone having the formula:

1 If s wherein R R R R and R are as given above. The photodimerization is advantageously effected in aqueous solution at room temperature (24 to 30 C.) because of the ease with which the dimers can be isolated. For the more insoluble Z-pyridones, an organic solvent, for example ethanol or other lower-alkanol, benzene, toluene, hexane, chloroform, carbon tetrachloride, diethyl ether or other di-lower-alkyl ethers, and the like, can be used. Higher or lower temperature, say from about 0 to about degrees centigrade can be used. The light source can be any ultraviolet lamp, filtered or unfiltered, giving 01f radiations in the range of about 240 to 260 millimicrons.

The starting compounds IV can be prepared by alkylating 2-pyridone by the procedure of Rath [Ann, 489, 107 (1931)], according to the following equation:

wherein Hal is halogen, e.g., chlorine, bromine, or iodine, and R R R R and R are as given above. Alternatively, they can be prepared by alkylating pyridine and oxidizing With alkali metal ferricyanide by the procedure 3 of US. Pat. 1,941,312 according to the following equations:

wherein Hal and R R R R and R are as given above. Another procedure that can be used is that of Bradlow and Vanderwerf [J. Org. Chem., 16, 73 (1951)] according to the following equations:

wherein R R R R and R are as given above.

The invention can now be more fully understood by reference to the following examples which are given by way of illustration and in which parts and percentages are by weight unless otherwise specified.

EXAMPLE 1 R :Metlzyl PAR/l A.3,7-DIME'1HYL-37 -DIAZATRICYCLO[4.2.2.225]

DODECA-9,11-DIENE-4,8-DIONE o A solution of g. (0.457 mole) of 1 methyl-2-(1H)- pyridone in 300 ml. of water was irradiated for 48 hr. at 25 C. with a 200 watt unfiltered mercury vapor ultraviolet lamp. The solution was extracted with three 150 ml. portions of methylene chloride and the combined organic layers were dried, filtered and evaporated. The residual material was treated with ethanol-ether (1:2) and cooled. The crystals were filtered, washed with ether and dried to give 21.6 g. (43.2%) of 3,7-dimethyl-3,7-diazatricyclo[4.2.2.2 ]dodeca-9,l1-diene-4,8 dione, M.P. ZZZ-222.5. Pure 3,7-dimethyl-3,7-diazatricyclo dodeca-9,11-diene-4,8-dione was obtained as fine white platelets from ethanol-ether, M.P. 222.5.

Analysis.Calcd for C H N O (percent): C, 66.03; H, 6.47; N, 12.84. Found (percent): C, 65.89; H, 6.27;

M.W.: Calcd 218; Found: 231. PART B.3,7-DIMETHYL-3-7-DIAZATRICYCLO [4.22.2

The consumption of hydrogen ceased after an uptake of 104% of theory. The catalyst was filtered and the filtrate concentrated. The dried residue was twice recrystallized from ethanol-ether to give 34.5 g. (94.7%) of white crystals of 3,7-dimethyl-3,7-diazatricyclo[4.2.2.2 ]dodecane- 4,8-dione, M.P. 284-285.

PART C.-3,7-DIMETHYL-3-Y-DIAZATRICYCLO[4.2.2.22'5] DODECANE DIHYDROCHLORIDE To a stirred slurry of 19.0 g. (0.50 mole) of lithium aluminum hydride in 350 ml. of dry, purified tetrahydrofuran was added in portions a slurry of 34.4 g. (0.154 mole) of the 3,7-dimethyl-3,7-diazatricyclo[4.2.2.2 ]dodecane-4,8-dione of Part B in 400 ml. of the same solvent. The resulting mixture was refluxed with stirring for 2 hr. and allowed to stand overnight at room temperature. To the rapidly stirred mixture cooled in ice, there was added 19 ml. of water, 57 ml. of 25% sodium hydroxide solution and 19 ml. of water in that order. The precipitated salts were filtered and washed well with ether and methylene chloride. The combined filtrates were dried, filtered and evaporated to give, after thorough drying, 29.4 g. (98.5%) of pale yellow solid which was converted directly to its dihydrochloride. Recrystallization from ethanol-ether gave pure 3,7-dimethyl-3,7-diazatricyclo [4.2.2.2 ]dodecane dihydrochloride as white blades, M.P. 274 (foaming).

Analysis.-Calcd for C H CI N (percent): C, 53.93; H, 9.05; N, 10.48. Found (percent): C, 54.04; H, 9.22; N, 10.34.

In the tests for pharmacodynamic activity in mice the dihydrochloride showed sedative activity.

PART D.3,7-DIMETHYL-3,7-DIAZATRICYCLO[4.2.2.225] DODECANE FREE BASE A 4.60 g. (0.017 mole) sample of the dihydrochloride was dissolved in 20 ml. of water and to the solution was added 50 ml. of concentrated ammonium hydroxide. The white solid which separated was extracted with two ml. portions of methylene chloride. The combined organic layers were dried, filtered and evaporated to afford 3.1 g. (94.0%) of 3,7 dimethyl 3,7 diazatricyclo- [4.2.2.2 ]dodecane free base as white prisms, M.P. 48- 48.5 (from hexane).

Analysis.-Calcd for C H N (percent): C, 74.17; H, 11.41; N, 14.42. Found (percent): C, 74.45; H, 11.12; N, 14.21.

EXAMPLE 2 R5 Ethyl 3,7-DIETHYL-3,7-DIAZATRICYCLO [4,22,2 DODECA- 9,11-DIENE-4,8DIONE A solution of 50.0 g. (0.406 mole) of 1-ethyl-2(1H)- pyridone in 300 ml. of Water was irradiated for 48 hr. at 25 with a 200 watt unfiltered mercury vapor ultraviolet lamp. The solution was extracted with three 200 ml. portions of methylene chloride. The combined organic layers were dried, filtered and evaporated. The white semi-solid was treated with benzene-hexane (1:1), and the crystals were filtered and dried to give 20.75 g. (41.5%) of 3,7 diethyl-3,7-diazatricyclo[4.2.2.2 ]dodeca-9,11-diene-4,8-dione as fluify white platelets, M.P. 208-209". The analytical sample was prepared by recrystallization of this material from ethanol-ether, shiny white platelets, M.P. 209-210.

Analysis.Calcd for C H N O (percent): C, 68.27; H, 7.37; N, 11.37. Found (percent): C, 68.50; H, 7.62; N, 11.34.

M.W.: Calcd 246; Found: 260.

In tests for pharmacodynamic activity in mice, this compound displayed antiappetite activity.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Part C, there are obtained 3,7-diethyl 3,7 diazatricyclo[4.2.2.2 ]dodecane-4,8-dione and 3,7-diethyl-3,7-diazatricyclo[4.2.2.2 ]dodecane free base and the dihydrochloride thereof.

EXAMPLE 3 PART A.-3,7-DIPROPYL-3,7-DIAZATRICYCLO[4.2.2.2 DODECA-9,11-DIENE4,8-DIONE A solution of 30.0 g. (0.218 mole) of 1-propyl-2(1H)- pyridone in 375 ml. of water was irradiated for 48 hr. as described above. The aqueous solution was extracted with two 250-ml. portions of methylene chloride and the combined organic layers were dried, filtered and evaporated. The semi-solid residue was treated with hexaneether (1:1), and the solid was separated by filtration and dried to give 8.85 g. (29.5%) of product, M.P. 198- 199. The pure photodimer, 3,7 dipropyl-3,7-diazatricyclo[4.2.2.2 ]dodeca 9,11 diene-4,8-dione, was obtained as white prisms from ethanol-ether, M.P. 199.

Analysis.Calcd for C H N O (percent): C, 70.04; H, 8.08; N, 10.21. Found (percent): C, 70.00; H, 8.02; N, 10.23.

M.W.: Calcd 274; Found: 272.

In tests for pharmacodynamic activity in mice, this compound displayed sedative and muscle relaxant activity.

PART B.-3,7-DIPROPYL-3,T-DIAZATRICYCLO[422.2 DODECANE-4,s-DIONE A 1.70 g. (.006 mole) sample of the photodimer of Part A in 50 ml. of ethanol containing 200 mg. of platinum oxide was hydrogenated in a Parr apparatus. The catalyst was filtered and the filtrate was concentrated to give 1.65 g. (97.0%) of 3,7-dipropyl-3,7-diazatricyclo- [4.2.2.2 ]dodecane-4,8-dione as a white solid, M.P. 203-206". Pure product was obtained as white prisms from ethanol-ether, M.P. 2102ll.

AnaIysis.Calcd for C H N O (percent): C, 69.03; H, 9.41; N, 10.06. Found (percent): C, 68.89; H, 9.11; N, 10.28.

In tests for pharmacodynamic activity in mice, this compound displayed sedative and antiinflammatory activities.

On treatment as in Example 1, Parts C and D, there are obtained 3,7-dipropyl-3,7-diazatricyclo[4.2.2.2 ]dodecane free base and the dihydrochloride thereof.

EXAMPLE 4 R =Isopropyl PART A.3,7-DIISOPROPYL-3,7-DIAZATRICYCLO [4.2.2.2 DODECA-9,ll-DIENE-4,8-DIONE A solution of 11.9 g. (0.087 mole) of l-isopropyl- 2(1H)-pyridone in 375 ml. of water was irradiated for 4 days as previously described. The aqueous solution was extracted with three 150-ml. portions of methylene chloride and the combined organic layers were dried, filtered and evaporated. The semi-crystalline residue was treated with benzene-hexane (1:1), filtered and dried to give 2.85 g. (24.0%) of white solid, M.P. ZZZ-224. Pure photodimer, 3,7 diisopropyl-3,7-diazatricyclo[4.2.2.2 dodeca-9,11-diene-4,8-dione, was obtained as white needles from benzene-ethanol-hexane, M.P. 228-229".

Analysis.Calcd for C H N O (percent): C, 70.04; H, 8.08; N, 10.21. Found (percent): C, 70.22; H, 8.30; N, 10.38.

M.W.: Calcd 274; Found: 285.

In tests for pharmacodynamic activity in mice, this compound displayed sedative and antiinfiammatory activities.

PART B.3,7-DIISOPROPYL-3,7-DIAZATRICYCLO [4.2.2.2 ]DODECANE-4,8-DIONE A solution of 1.40 g. (5.1 moles) of the photodimer of Part A in 150 ml. of ethanol containing 100 mg. of platinum oxide was hydrogenated in a Parr apparatus. The consumption of hydrogen ceased after the uptake of 98% of theory. The catalyst was filtered and the filtrate concentrated. The dried residue (1.40 g., 99%), M.P. 232-236, was twice recrystallized from ethanol-ether to 6 give 3,7 diisopropyl 3,7 diazatricyclo[4.2.2.2 ]dodecane-4,8-dione as shiny white platelets, M.P. 247-249".

Analysis.-Calcd for C H N O (percent): C, 69.03; H, 9.41; N, 10.06. Found (percent): C, 69.05; H, 9.19; N, 9.90.

In tests for pharmacodynamic activity in mice, this compound showed CNS stimulant activity.

On reduction as in Example 1, Part C, there are obtained 3,7-diisopropyl 3,7 diazatricyclo[4.2.2.2 ]dodecane free base and the dihydrochloride thereof.

EXAMPLE 5 R z2-Hydro xyethyl PART 'A.3,7-BIS (2-HYDROXYETHYL-3,7-DIAZATRI- 'CYCL0[4.2.2.2 ]DODECA-9,11-DIENE-4,S-DIONEI A solution of 56.5 g. (0.40 mole) of 1-(2-hydroxyethyl)-2(1H)-pyridone in 300 ml. of water was irradiated for 16 hr. as described previously. The precipitated white solid was filtered, washed with ethanol and dried to give 10.5 g. (18.6%) of dimer, 3,7-bis(2-hydr0xyethyl)-3,7- diazatricyclo[4.2.2.2 ]-dodeca-9,11-diene-4,8-dione, M.P. 225228. Recrystallization of this material from water afforded pure product as fine white micro crystals, M.P. 229.

Analysis.Calcd for C H N O (percent): C, 60.42; H, 6.52; N, 10.07. Found (percent): C, 60.45; H, 6.88; N, 9.98.

In tests for pharmacodynamic activity in mice, this compound displayed sedative and antiappetite activities.

PART B.3,7-BIS(2-HYDROXYETHYL-3,7-DIAZATrRI- CYCLO[4.2.-2.2=""]DODECANE-4,S-DIONE A solution of 5.5 g. (0.02 mole) of the photodimer of Part A in 150 ml. of acetic acid-water (2:1) containing 250 mg. of platinum oxide was hydrogenated in a Parr bomb. Hydrogen uptake ceased after the consumption of of theory. The catalyst was filtered and the filtrate was evaporated under reduced pressure. Ethanol (50 ml.) was added and also evaporated. After thorough drying of the residue, there was obtained 5.5 g. (100%) of white solid, M.P. 229-230. Recrystallization of this material from water gave the analytical sample as a fine white powder, M.P. 230-231.5.

Analysis.Calcd for C H N O (percent): C, 59.55; H, 7.85; N, 9.92. Found (percent): C, 59.57; H, 7.56; N, 10.10.

In tests for pharmacodynamic activity in mice, this compound displayed antiappetite activity.

On reduction as in Example 1, Part C, there are obtained 3,7 bis(2 hydroxyethyl) 3,7 diazatricyclo [4.2.2.2 ]dodecane free base and the dihydrochloride thereof.

EXAMPLE 6 R =Anisyl (p-methoxybenzyl) PART A.1-(i-METHOXYBENZYL)-2-(1H)PYRIDONE A mixture of 15.7 g. (0.10 mole) of anisyl chloride and 18.5 g. (0.15 mole) of 2-ethoxypyridine was heated with stirring at for 24 hrs. The material was chromatographed directly on magnesium silicate. Elution with hexane removed the starting materials and elution with ether afforded 21.5 g. (100%) of white crystals, M.P. 8486, after drying. Pure 1-(4-methoxybenzyl)-2(1H)- pyridone was obtained as fluffy white needles from benzene-hexane, M.P. 84.586.

Analysis.-Calcd for C H NO (percent): C, 72.54; H, 6.09; N, 6.51. Found (percent): C, 72.45; H, 5.79; N, 6.60.

PART B.3,7BIS (P-METHOXYBENZYL) -3,7DIAZATRI- CYCLO [4.2.2.2 DODECA-9,11-DIENE4,8-DIONE A solution of 40 g. (0.186 mole) of the pyridone of Part A in 400 ml. of 50% aqueous ethanol was irradiated for 20 hrs. as previously described. The precipitated solid was filtered and the filtrate was reirradiated for 23 hrs.

7 There was obtained a total of 5.2 g. (13.0%) of greyish solid, M.P. 228-232. Three recrystallizations of this material from dimethylformamide gave pure photodimer, 3,7-bis(p-methoxybenzyl)-3,7 diazatricyclo [4.2.2.2 dodeca-9,11-diene-4,8-dione, as White platelets, M.P. 232.

Analysis.-Calcd for C H N O (percent): C, 72.54; H, 6.09; N, 6.51. Found (percent): C, 72.22; H, 5.93; N, 6.80.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Part C, there are obtained 3,7-bis(pmethoxybenzyl) 3,7 diazatricyclo[4.2.2.2 ]dodecane- 4,8-dione and 3,7-bis(p-methoxybenzyl)-3,7-diazatricyclo [4.2.2.2 ]dodecane free base and the dihydrochloride thereof.

By substituting the anisyl chloride in Example 6 by the appropriate R Cl or R Br, for example, where R is 2- methoxybenzyl, 3-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, benzyl, phenethyl, l-phenethyl, 3- phenylpropyl 2-, 3- and 4-methoxy(3-phenylpropyl)-3,4- dimethoxy(3-phenylpropyl) 3,4,5 trimethoxy(3-phenylpropyl) cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bornyl, fenchyl, and 3-cyclopentylpropyl, there are obtained the corresponding 3,7-bis (R )-3,7-diazatricyclo [4.2.2.2 ]dodeca-9,11 diene 4,8- diones; 3,7 bis(R 3,7-diazatricyclo[4.2.2.2 ]dodecane 4,8 diones; and 3,7 bis(R 3,7 diazatricyclo [4.2.2.2 ]dodecanes.

EXAMPLE 7 R1 and PART A.METI-IYL2 (1H)'PYRIDONE This material was prepared by the method of R. Adams and A. W. Schrecker [1. Am. Chem. Soc., 71, 1186 (1948)]. Diazotization of 216 g. (2.0 moles) of 2-amin0- G-methyplyridine afforded 184 g. (84.5%) of the pyridone, large white crystals from benzene, M.P. 158-159".

PART B.-1,6-DIMETHYL-2 (1H) -IYRIDONE This material was prepared by the method of R. Adams and A. W. Schrecker [1. Am. Chem. Soc., 71, 1176 (1949)]. Methylation of 173.5 g. (1.59 moles) of 6-methyl-2(1H)-pyridone with dimethyl sulfate aiforded 130 g. (66.3%) of deliquescent white crystals (from ether), M.P. 56-5 8.

PART C.2,3,6,7-TETRAMETHYL-3,7-DIAZATRICYCLO [4.2.2.2155]DODECA-9,11-DIENE-4,S'DIONE A solution of 40.0 g. (0.325 mole) of 1,6-dimethy1- 2(1H)-pyridone of Part B in 300 ml. of water was irradiated for 24 hrs. as previously described. The precipitated solid was filtered and dried to give 19.0 g. of dimer. From methylene chloride extracts of the filtrate, there was obtained an additional 1.8 g. of dimer, 2,3,6,7-tetramethyl- 3,7-diazatricyclo[4.2.2.2 ]ddeca-9,1l-diene 4,8 dione (total yield, 20.8 g., 52.0%) M.P. 200-201". The analytical sample was obtained as fluflFy white microneedles from ethanol-ether, M.P. 201-201.5 C.

Analysis.--Calcd for C H N O (percent): C, 68.27; H, 7.37; N, 11.37. Found (percent): C, 68.55; H, 7.20; N, 10.98.

M.W.: Calcd 246; Found: 246.

In tests for pharmacodynamic activity in mice, this compound displayed antiappetite activity and caused an increase in body fat.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Part C, there are obtained 2,3,6,7- tetramethyl 3,7 diazatricyclo[4.2.2.2 dodecane 4,8- dione, and 2,3,6,7-tetramethyl-3,7-diazatricyclo[4.2.2.2 dodecane free base and the dihydrochloride thereof.

EXAMPLE 8 R and R =Methyl PART A.-5-METHYL-2 (1H)-PYRIDONE This material was prepared by the method of H. L. Bradlow and C. A. Vanderwerf [J. Org. Chem, 16, 73

(1951)]. Diazotization of 216 g. (2.0 moles) of 2-amino- S-methyl-pyridine afforded 44.0 g. (21.0%) of White crys tals, M.P. 181182.

PART B.1,5-DIl\IETHYL-=2 (1H) -IYRIDONE This material Was prepared by the method of H. L. Bradlow and C. A. Vanderwerf (loc. cit.). Methylation of 40.0 g. (0.366 mole) of 5-methyl-2(1H)-pyridone afforded 36.5 g. (81.0%) of colorless distillate, B.P. 88- 92 (0.5 mm.).

PART C.-3,7,10,12-TETRAMETHYL3,7-DIAZATRICYCLO [4.2.2.2 ]DODECA-Q,ll-DIENE-4,S-DIONE A solution of 30.0 g. (0.244 mole) of 1,5-dimethyl- 2(lH)-pyridone in 300 ml. of water was irradiated for 16 hr. as previously described. The precipitated solid was filtered, washed with ether and dried to give 13.6 g. of white crystals, M.P. 239241. Methylene chloride extraction of the filtrate afforded an additional 3.9 g. of dimer, M.P. 185-227" (total yield, 17.5 g., 58.3%). Pure photodimer, 3,7,10,12-tetramethyl-3,7-diazatricyclo [4.2.2.2 dodeca-9,11-diene-4,8-dione, was obtained as shiny white platelets from aqueous ethanol-ether, M.P. 24024l.

Analysis.Calcd for C I-1 N 0 (percent): C, 68.27; H, 7.37; N, 11.37. Found (percent): C, 68.00; H, 7.52; N, 11.08.

M.W.: Calcd 246; Found: 299.

In pharmacodynamic tests 'With mice, this compound displayed antiappetite activity.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Par-t C, there are obtained 3,7,10,12- tetramethyl 3,7 diazatricyclo[4.2.2.2 ]dodecane-4,8- dione, and 3,7,10,12 tetramethyl 3,7 diazatricyclo [4.2.2.f2 ]dodecane free base and the dihydrochloride thereo EXAMPLE 9 R and R =Methyl PART A.4-METHYL2 (1H) -PYRIDON E This material was prepared by the method of R. Adams and A. W. Schrecker [1. Am. Chem. Soc., 71, 1186 (1949)]. Diazotization of 216 g. (2.0 moles) of Z-amino- 4-methylpyridine afforded 140 g. (64.6%) of the White crystalline pyridone, M.P. 124-125 PART B.-1,4-DIMETHYL-2 (1H) -PYRIDONE This material was prepared by the method of R. Adams and A. W. Schrecker (loc. cit.). Methylation of 132 g. (1.21 moles) of 4-methyl-2(1H)-pyridone aiforded 134 g. (90.0%) of a deliquescent solid, B.P. 95-98 (0.75 mm.), M.P. 57-59.

'PARI C.-3,7,9,11-TETRAMETHYL 3,7-DIAZATRICYCLO [4.2.2.2 DODECA-Q,11-DIENE-4,8-DIONE A solution of 40.0 g. (0.325 mole) of 1,4-dimethyl- 2(lH)-pyridone in 300 ml. of water was irradiated for 16 hr. as previously described. The precipitated solid was filtered, washed with water and dried to give 3.85 g. of dimer, M.P. 240. Methylene chloride extraction of the filtrate afforded an additional 3.75 g., M.P. 235-238 (total yield 7.6 g., 19.0%). Pure photodimer, 3,7,9,l1- tetramethyl 3,7 diazatricyclo[4.2.2.2 ]dodeca 9,11- diene-4,8-dione, was obtained as white prisms from ethanol-ether, M.P. 241.

Analysis.Calcd for C H N O (percent): C, 68.27; H, 7.37; N, 11.37. Found (percent): C, 68.09; H, 7.03; N, 11.18.

M.W.: Calcd 246; Found: 239.

In tests for pharmacodynamic activity in mice this compound displayed antiappetite activity.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Part C, there are obtained 3,7,9,11- tetramethyl 3,7 diazatricyclo[4.2.2.2 ]dodecane-4,8- dione, and 3,7,9,11 tetramethyl 3,7 diazatricyclo 9 [4.2.2.2 ]dodecane free base and the dihydrochlori-de thereof.

EXAMPLE 10 R and R =Methyl PART A.3-lVIETHYL-2 (1H) -PYRIDONE This material was prepared by the method of H. L. Bradlow and C. A. Vanderwerf [J. Org. Chem., 16, 73 (1951)]. Diazotization of 216 g. (2.0 moles) of 2-amino- 3-methyl-pyridine alforded 157 g. (72.0%) of the white crystalline pyridone, M.P. 139-140.

PART B.1,8-DIMETHYL-2 (1H) -PYRIDONE This material was prepared by the method of H. L. Bradlow and C. A. Vanderwerf [J. Org. Chem, 16, 73 (1951)]. Methylation of 150 g. (1.37 moles) of 3-methyl-2(1H)-pyridone afforded 134 g. (79.7%) of colorless liquid, B.P. 83-86" (0.75 mm.), n 1.5538.

PART C.-l.3.5.7-TETRAMETHYL-3,Y-DIAZATRICYCLO- [4.2.2.2 DODECA-9,11-DIENE4,8-DIONE A solution of 40.0 g. (0.325 mole) of 1,3-dimethyl- 2(lH)-pyridone in 300 ml. of water was irradiated for 16 hr. as previously described. The precipitated solid was filtered, washed with ice water and dried to give 3.60 g. of dimer, M.P. 191. Methylene chloride extraction of the filtrate afforded an additional 2.15 g., M.P. 191 (total yield 5.75 g., 14.4% Pure photodimer, 1,3,5,7-tetramethyl 3,7-diazatricyclo[4.2.2.2 ]dodeca-9,11-diene- 4,8-dione, was obtained as white platelets from ethanolether, M.P. 191.

Analysis.Calcd for C H N O (percent): C, 68.27; H, 7.37; N, 11.37. Found (percent): C, 68.17; H, 7.32; N, 11.14.

M.W.: Calcd 246; Found: 237.

In tests for pharmacodynamic activity in mice, this compound displayed CNS stimulant activity and antiappetite activity.

On hydrogenation as in Example 1, Part B, and reduction as in Example 1, Part C, there are obtained 1,3,5,7- tetramethyl-3,7 diazatricyclo[4.2.2.2 ]dodecane 4,8- dione, and 1,3,5,7-tetramethyl-3,7-diazatricyclo[4.2.2.2 dodecane free base and the hydrochloride thereof.

Following the procedures of Examples 7, 8, 9, and 10 substituting other methyl and ethyl substituted Z-aminopyridines there are obtained compounds in which any or all of R R R and R, can be methyl or ethyl. Also by substituting other alkylating agents R can be any of the radicals disclosed above in connection with Formula I.

EXAMPLE 11 PART A.3,3,7-TRIl\IETHYL-7-AZA-3-AZONIATRICYCLO [4.2.2.2 ]D0DECANE DIIODIDE A solution of 14.0 g. (0.072 mole) of the diamine of Part C, Example 1, in 150 ml. of ethanol was treated with 56.8 g. (0.40 mole) of methyl iodide and the solution was refluxed for 3 hr. Ether (100 ml.) was added and the mixture was cooled. The precipitated solid was filtered and dried to give 23.6 g. (97.7%) of pale yellow solid, M.P. 208212. (dec.). This material was recrystallized 10 three times from ethanol to give pure 3,3,7-trimethyl-7- aza-3-azoniatricyclo [4.2.2.2 dodecane iodide as a white solid, M.P. 214-215 (dec.).

Analysis.Calcd for C H IN (percent): C, 46.43; H, 7.49; N, 8.33. Found (percent): C, 46.15; H, 7.32; N, 8.14.

In tests for pharmacodynamic activity in mice, this compound displayed diuretic activity.

PART B.-3,3,7,7-TETRAMETHYL-3,7-DIAZONIATRICYCLO [4.2.2.2 JDODECANE DIIODIDE A slurry of 10.0 g. (0.0298 mole) of the monomethiodide of lart A in ml. of methyl iodide was heated in an autoclave at -130 for 8 hr. The solvent was evaporated and the gummy residue was recrystallized from 90% ethanol-ether. The crystals which formed were filtered and dried to yield 7.6 g. (53.5%) of 3,3,7,7-tetramethyl 3,7-diazoniatricyclo[4.2.2.2 dodecane diiodide, M.P. 205-206.5. The analytical sample was prepared by recrystallization of this material from 75% ethanol, white powder, M.P. 212 (dec.).

Analysis.Calcd for C H I N (percent): C, 35.16; H, 5.90; N, 5.86. Found (percent): C, 34.85; H, 5.91; N, 5.52.

In tests for pharmacodynamic activity this compound displayed CNS stimulant activity.

All the compounds described above, except those having methyl and ethyl substituents in the two and six positions, have point symmetry.

I claim:

1. 3,7 bis(2 hydroxyethyl) 3,7 diazatricyclo [4.2.2.2 dodecane 4,8 dione.

2. 3,7 bis(2 hydroxyethyl) 3,7 diazatricyclo [4.2.2.2 dodeca 9,11 diene 4,8 dione.

3. 3,7 bis(p methoxybenzyl) 3,7 diazatricyclo [4.2.2.2 dodeca-9,11-diene-4,8-dione.

References Cited UNITED STATES PATENTS 2,800,484 7/1957 Stoll et a1. 260-294] 2,991,288 7/ 1961 Farstrap et a1. 260293 3,078,272 2/1963 Mull 260293 3,118,900 1/1964 Yaugg et al. 260294.7

OTHER REFERENCES Slomp et al.: Jour. Am. Chem. Soc., vol. 83, pp. 4472-4 (November 1961), QD 145.

Ayer et al.: Tetrahedron Letters, pp. 648-653 (September 1961), QD241 T42.

NORMA S. MILESTONE, Primary Examiner US. Cl. X.R. 

1. 3,7 - BIS(2-HYDROXYETHYL)-3,7-DIAZATRICYCLO(4.2.2.2**2,**5)DODECANE-4,8-DIONE. 